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1دورية أكاديمية
المؤلفون: Sjúrðarson, Tórur, Kristiansen, Jacobina, Nordsborg, Nikolai B., Gregersen, Noomi O., Lydersen, Leivur N., Grove, Erik L., Kristensen, Steen D., Hvas, Anne Mette, Mohr, Magni
المصدر: Sjúrðarson , T , Kristiansen , J , Nordsborg , N B , Gregersen , N O , Lydersen , L N , Grove , E L , Kristensen , S D , Hvas , A M & Mohr , M 2023 , ' The angiotensin-converting enzyme I/D polymorphism does not impact training-induced adaptations in exercise capacity in patients with stable coronary artery disease ' , Scientific Reports , vol. 13 , no. 1 , 18300 . https://doi.org/10.1038/s41598-023-45542-0Test
مصطلحات موضوعية: Angiotensins/genetics, Coronary Artery Disease/genetics, Exercise Tolerance/genetics, Female, Genotype, Humans, Male, Oxygen, Peptidyl-Dipeptidase A/genetics, Polymorphism, Genetic
الوصف: Systematic exercise training effectively improves exercise capacity in patients with coronary artery disease (CAD), but the magnitude of improvements is highly heterogeneous. We investigated whether this heterogeneity in exercise capacity gains is influenced by the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene. Patients with CAD (n = 169) were randomly assigned to 12 weeks of exercise training or standard care, and 142 patients completed the study. The ACE polymorphism was determined for 128 patients (82% males, 67 ± 9 years). Peak oxygen uptake was measured before and after the 12-week intervention. The ACE I/D polymorphism frequency was n = 48 for D/D homozygotes, n = 61 for I/D heterozygotes and n = 19 for I/I homozygotes. Baseline peak oxygen uptake was 23.3 ± 5.0 ml/kg/min in D/D homozygotes, 22.1 ± 5.3 ml/kg/min in I/D heterozygotes and 23.1 ± 6.0 ml/kg/min in I/I homozygotes, with no statistical differences between genotype groups (P = 0.50). The ACE I/D polymorphism frequency in the exercise group was n = 26 for D/D, n = 21 for I/D and n = 12 for I/I. After exercise training, peak oxygen uptake was increased (P < 0.001) in D/D homozygotes by 2.6 ± 1.7 ml/kg/min, in I/D heterozygotes by 2.7 ± 1.9 ml/kg/min, and in I/I homozygotes by 2.1 ± 1.3 ml/kg/min. However, the improvements were similar between genotype groups (time × genotype, P = 0.55). In conclusion, the ACE I/D polymorphism does not affect baseline exercise capacity or exercise capacity gains in response to 12 weeks of high-intensity exercise training in patients with stable CAD. Clinical trial registration: www.clinicaltrials.gov (NCT04268992).
الإتاحة: https://doi.org/10.1038/s41598-023-45542-0Test
https://pure.au.dk/portal/en/publications/32d02ed2-8600-4a44-980e-2fffb1b4c0bcTest
http://www.scopus.com/inward/record.url?scp=85174922364&partnerID=8YFLogxKTest -
2دورية أكاديمية
المؤلفون: Yarmolinsky, James, Díez-Obrero, Virginia, Richardson, Tom G, Pigeyre, Marie, Sjaarda, Jennifer, Paré, Guillaume, Walker, Venexia M, Vincent, Emma E, Tan, Vanessa Y, Obón-Santacana, Mireia, Albanes, Demetrius, Hampe, Jochen, Gsur, Andrea, Hampel, Heather, Pai, Rish K, Jenkins, Mark, Gallinger, Steven, Casey, Graham, Zheng, Wei, Amos, Christopher I, Smith, George Davey, Martin, Richard M, Moreno, Victor
المصدر: Yarmolinsky , J , Díez-Obrero , V , Richardson , T G , Pigeyre , M , Sjaarda , J , Paré , G , Walker , V M , Vincent , E E , Tan , V Y , Obón-Santacana , M , Albanes , D , Hampe , J , Gsur , A , Hampel , H , Pai , R K , Jenkins , M , Gallinger , S , Casey , G , Zheng , W , Amos , C I , International Lung Cancer Consortium , The PRACTICAL Consortium , The MEGASTROKE consortium , ....
مصطلحات موضوعية: Antihypertensive Agents/adverse effects, Blood Pressure/drug effects, Female, Genome-Wide Association Study/methods, Humans, Male, Mendelian Randomization Analysis/methods, Neoplasms/chemically induced, Peptidyl-Dipeptidase A/genetics, Polymorphism, Single Nucleotide/drug effects, Receptors, Adrenergic, beta-1/genetics, Risk Factors, Solute Carrier Family 12, Member 3/genetics
الوصف: BACKGROUND: Epidemiological studies have reported conflicting findings on the potential adverse effects of long-term antihypertensive medication use on cancer risk. Naturally occurring variation in genes encoding antihypertensive drug targets can be used as proxies for these targets to examine the effect of their long-term therapeutic inhibition on disease outcomes. METHODS AND FINDINGS: We performed a mendelian randomization analysis to examine the association between genetically proxied inhibition of 3 antihypertensive drug targets and risk of 4 common cancers (breast, colorectal, lung, and prostate). Single-nucleotide polymorphisms (SNPs) in ACE, ADRB1, and SLC12A3 associated (P < 5.0 × 10-8) with systolic blood pressure (SBP) in genome-wide association studies (GWAS) were used to proxy inhibition of angiotensin-converting enzyme (ACE), β-1 adrenergic receptor (ADRB1), and sodium-chloride symporter (NCC), respectively. Summary genetic association estimates for these SNPs were obtained from GWAS consortia for the following cancers: breast (122,977 cases, 105,974 controls), colorectal (58,221 cases, 67,694 controls), lung (29,266 cases, 56,450 controls), and prostate (79,148 cases, 61,106 controls). Replication analyses were performed in the FinnGen consortium (1,573 colorectal cancer cases, 120,006 controls). Cancer GWAS and FinnGen consortia data were restricted to individuals of European ancestry. Inverse-variance weighted random-effects models were used to examine associations between genetically proxied inhibition of these drug targets and risk of cancer. Multivariable mendelian randomization and colocalization analyses were employed to examine robustness of findings to violations of mendelian randomization assumptions. Genetically proxied ACE inhibition equivalent to a 1-mm Hg reduction in SBP was associated with increased odds of colorectal cancer (odds ratio (OR) 1.13, 95% CI 1.06 to 1.22; P = 3.6 × 10-4). This finding was replicated in the FinnGen consortium (OR 1.40, 95% CI 1.02 to 1.92; P = ...
الإتاحة: https://doi.org/10.1371/journal.pmed.1003897Test
https://pure.au.dk/portal/en/publications/0557a58f-fabf-43cd-a18c-672119976ad6Test -
3دورية أكاديمية
المؤلفون: Fernández-de-las-Peñas, César, Arendt-Nielsen, Lars, Díaz-Gil, Gema, Gómez-Esquer, Francisco, Gil-Crujera, Antonio, Gómez-Sánchez, Stella M., Ambite-Quesada, Silvia, Palomar-Gallego, María A., Pellicer-Valero, Oscar J., Giordano, Rocco
المصدر: Fernández-de-las-Peñas , C , Arendt-Nielsen , L , Díaz-Gil , G , Gómez-Esquer , F , Gil-Crujera , A , Gómez-Sánchez , S M , Ambite-Quesada , S , Palomar-Gallego , M A , Pellicer-Valero , O J & Giordano , R 2022 , ' Genetic Association between ACE2 (rs2285666 and rs2074192) and TMPRSS2 (rs12329760 and rs2070788) Polymorphisms with Post-COVID Symptoms in Previously Hospitalized COVID-19 Survivors ' , genes , vol. 13 , no. 11 , 1935 . https://doi.org/10.3390/genes13111935Test
مصطلحات موضوعية: ACE2, Adult, Aged, Angiotensin-Converting Enzyme 2/genetics, COVID-19/genetics, Female, Humans, Male, Middle Aged, Peptidyl-Dipeptidase A/genetics, Polymorphism, Single Nucleotide, SARS-CoV-2, Serine Endopeptidases/genetics, Survivors, TMPRSS2, long-covid, post-covid, single nucleotide polymorphism
الوصف: The aim of the study was to identify the association between four selected COVID-19 polymorphisms of ACE2 and TMPRSS2 receptors genes with the presence of long-COVID symptomatology in COVID-19 survivors. These genes were selected as they associate with the entry of the SARS-CoV-2 virus into the cells, so polymorphisms could be important for the prognoses of long-COVID symptoms. Two hundred and ninety-three (n = 293, 49.5% female, mean age: 55.6 ± 12.9 years) individuals who had been previously hospitalized due to COVID-19 were included. Three potential genotypes of the following single nucleotide polymorphisms (SNPs) were obtained from non-stimulated saliva samples of participants: ACE2 (rs2285666), ACE2 (rs2074192), TMPRSS2 (rs12329760), TMPRSS2 (rs2070788). Participants were asked to self-report the presence of any post-COVID defined as a symptom that started no later than one month after SARS-CoV-2 acute infection and whether the symptom persisted at the time of the study. At the time of the study (mean: 17.8, SD: 5.2 months after hospital discharge), 87.7% patients reported at least one symptom. Fatigue (62.8%), pain (39.9%) or memory loss (32.1%) were the most prevalent post-COVID symptoms. Overall, no differences in long-COVID symptoms were dependent on ACE2 rs2285666, ACE2 rs2074192, TMPRSS2 rs12329760, or TMPRSS2 rs2070788 genotypes. The four SNPs assessed, albeit previously associated with COVID-19 severity, do not predispose for developing long-COVID symptoms in people who were previously hospitalized due to COVID-19 during the first wave of the pandemic.
وصف الملف: application/pdf
الإتاحة: https://doi.org/10.3390/genes13111935Test
https://vbn.aau.dk/da/publications/2f44624f-2c1a-468a-a6e5-c05d8c48c91dTest
https://vbn.aau.dk/ws/files/498358353/genes_13_01935.pdfTest
http://www.scopus.com/inward/record.url?scp=85141764776&partnerID=8YFLogxKTest -
4دورية أكاديمية
المصدر: http://lobid.org/resources/99370675515506441Test#!, 25(9-10):730-746.
مصطلحات موضوعية: Acetylcholinesterase, Insect, Hypoxia/genetics [MeSH], Brain/pathology [MeSH], Hypoxia, Non-synaptic, Insecta/genetics [MeSH], Neurons/metabolism [MeSH], Insecta/metabolism [MeSH], Acetylcholinesterase/genetics [MeSH], Apoptosis, Animals [MeSH], Article, Brain/metabolism [MeSH], Peptidyl-Dipeptidase A/genetics [MeSH], Grasshoppers/metabolism [MeSH], Cell Nucleus/genetics [MeSH], Neurons/pathology [MeSH], DNA Fragmentation [MeSH], Grasshoppers/genetics [MeSH], Apoptosis/genetics [MeSH], Cell Death/genetics [MeSH], Hypoxia/metabolism [MeSH]
الوصف: Apoptosis plays a major role in development, tissue renewal and the progression of degenerative diseases. Studies on various types of mammalian cells reported a pro-apoptotic function of acetylcholinesterase (AChE), particularly in the formation of the apoptosome and the degradation of nuclear DNA. While three AChE splice variants are present in mammals, invertebrates typically express two ache genes that code for a synaptically located protein and a protein with non-synaptic functions respectively. In order to investigate a potential contribution of AChE to apoptosis in insects, we selected the migratory locust Locusta migratoria. We established primary neuronal cultures of locust brains and characterized apoptosis progression in vitro. Dying neurons displayed typical characteristics of apoptosis, including caspase-activation, nuclear condensation and DNA fragmentation visualized by TUNEL staining. Addition of the AChE inhibitors neostigmine and territrem B reduced apoptotic cell death under normal culture conditions. Moreover, both inhibitors completely suppressed hypoxia-induced neuronal cell death. Exposure of live animals to severe hypoxia moderately increased the expression of ace-1 in locust brains in vivo. Our results indicate a previously unreported role of AChE in insect apoptosis that parallels the pro-apoptotic role in mammalian cells. This similarity adds to the list of apoptotic mechanisms shared by mammals and insects, supporting the hypothesized existence of an ancient, complex apoptosis regulatory network present in common ancestors of vertebrates and insects.
العلاقة: https://repository.publisso.de/resource/frl:6470658Test; https://doi.org/10.1007/s10495-020-01630-4Test; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527371Test/
الإتاحة: https://doi.org/10.1007/s10495-020-01630-4Test
https://repository.publisso.de/resource/frl:6470658Test
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527371Test/ -
5دورية أكاديمية
المؤلفون: Lamers, Mart M, Beumer, Joep, van der Vaart, Jelte, Knoops, Kèvin, Puschhof, Jens, Breugem, Tim I, Ravelli, Raimond B G, Paul van Schayck, J, Mykytyn, Anna Z, Duimel, Hans Q, van Donselaar, Elly, Riesebosch, Samra, Kuijpers, Helma J H, Schippers, Debby, van de Wetering, Willine J, de Graaf, Miranda, Koopmans, Marion, Cuppen, Edwin, Peters, Peter J, Haagmans, Bart L, Clevers, Hans
المساهمون: CMM, CMM Groep Cuppen, Cancer, CMM Sectie Molecular Cancer Research, Child Health, Regenerative Medicine and Stem Cells, Hubrecht Institute with UMC
مصطلحات موضوعية: Betacoronavirus/physiology, Cell Culture Techniques, Cell Differentiation, Cell Lineage, Cell Proliferation, Culture Media, Enterocytes/metabolism, Gene Expression, Humans, Ileum/metabolism, Lung/virology, Male, Organoids, Peptidyl-Dipeptidase A/genetics, RNA, Messenger/genetics, Receptors, Virus/genetics, Respiratory Mucosa/virology, SARS Virus/physiology, Virus Replication, General, Journal Article, Research Support, Non-U.S. Gov't
الوصف: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause coronavirus disease 2019 (COVID-19), an influenza-like disease that is primarily thought to infect the lungs with transmission through the respiratory route. However, clinical evidence suggests that the intestine may present another viral target organ. Indeed, the SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) is highly expressed on differentiated enterocytes. In human small intestinal organoids (hSIOs), enterocytes were readily infected by SARS-CoV and SARS-CoV-2, as demonstrated by confocal and electron microscopy. Enterocytes produced infectious viral particles, whereas messenger RNA expression analysis of hSIOs revealed induction of a generic viral response program. Therefore, the intestinal epithelium supports SARS-CoV-2 replication, and hSIOs serve as an experimental model for coronavirus infection and biology.
وصف الملف: application/pdf
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6دورية أكاديمية
المؤلفون: Ziegler, Carly G K, Allon, Samuel J, Nyquist, Sarah K, Mbano, Ian M, Miao, Vincent N, Tzouanas, Constantine N, Cao, Yuming, Yousif, Ashraf S, Bals, Julia, Hauser, Blake M, Feldman, Jared, Muus, Christoph, Wadsworth, Marc H, Kazer, Samuel W, Hughes, Travis K, Doran, Benjamin, Gatter, G James, Vukovic, Marko, Taliaferro, Faith, Mead, Benjamin E, Guo, Zhiru, Wang, Jennifer P, Gras, Delphine, Plaisant, Magali, Ansari, Meshal, Angelidis, Ilias, Adler, Heiko, Sucre, Jennifer M S, Taylor, Chase J, Lin, Brian, Waghray, Avinash, Mitsialis, Vanessa, Dwyer, Daniel F, Buchheit, Kathleen M, Boyce, Joshua A, Barrett, Nora A, Laidlaw, Tanya M, Carroll, Shaina L, Colonna, Lucrezia, Tkachev, Victor, Peterson, Christopher W, Yu, Alison, Zheng, Hengqi Betty, Gideon, Hannah P, Winchell, Caylin G, Lin, Philana Ling, Bingle, Colin D, Snapper, Scott B, Kropski, Jonathan A, Theis, Fabian J
المصدر: HCA Lung Biological Network. Electronic address: lung-network@humancellatlas.org , Ziegler , C G K , Allon , S J , Nyquist , S K , Mbano , I M , Miao , V N , Tzouanas , C N , Cao , Y , Yousif , A S , Bals , J , Hauser , B M , Feldman , J , Muus , C , Wadsworth , M H , Kazer , S W , Hughes , T K , Doran , B , Gatter , G J , Vukovic , M , Taliaferro , F , Mead , ....
مصطلحات موضوعية: Adolescent, Alveolar Epithelial Cells/immunology, Animals, Betacoronavirus/physiology, Cell Line, Cells, Cultured, Child, Coronavirus Infections/virology, Enterocytes/immunology, Goblet Cells/immunology, HIV Infections/immunology, Humans, Influenza, Human/immunology, Interferon Type I/immunology, Lung/cytology, Macaca mulatta, Mice, Mycobacterium tuberculosis, Nasal Mucosa/cytology, Pandemics, Peptidyl-Dipeptidase A/genetics, Pneumonia, Viral/virology, Receptors, Virus/genetics, Serine Endopeptidases/metabolism, Single-Cell Analysis, Tuberculosis/immunology
الوصف: There is pressing urgency to understand the pathogenesis of the severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2), which causes the disease COVID-19. SARS-CoV-2 spike (S) protein binds angiotensin-converting enzyme 2 (ACE2), and in concert with host proteases, principally transmembrane serine protease 2 (TMPRSS2), promotes cellular entry. The cell subsets targeted by SARS-CoV-2 in host tissues and the factors that regulate ACE2 expression remain unknown. Here, we leverage human, non-human primate, and mouse single-cell RNA-sequencing (scRNA-seq) datasets across health and disease to uncover putative targets of SARS-CoV-2 among tissue-resident cell subsets. We identify ACE2 and TMPRSS2 co-expressing cells within lung type II pneumocytes, ileal absorptive enterocytes, and nasal goblet secretory cells. Strikingly, we discovered that ACE2 is a human interferon-stimulated gene (ISG) in vitro using airway epithelial cells and extend our findings to in vivo viral infections. Our data suggest that SARS-CoV-2 could exploit species-specific interferon-driven upregulation of ACE2, a tissue-protective mediator during lung injury, to enhance infection. Analysis of single-cell RNA-seq datasets from human, non-human primate, and mouse barrier tissues identifies putative cellular targets of SARS-CoV-2 on the basis of ACE2 and TMPRSS2 expression. ACE2 represents a previously unappreciated interferon-stimulated gene in human, but not mouse, epithelial tissues, identifying anti-viral induction of a host tissue-protective mechanism, but also a potential means for viral exploitation of the host response.
وصف الملف: application/pdf
الإتاحة: https://doi.org/10.1016/j.cell.2020.04.035Test
https://hdl.handle.net/11370/99f61372-7873-4e72-b43f-2bd8816e9266Test
https://research.rug.nl/en/publications/99f61372-7873-4e72-b43f-2bd8816e9266Test
https://pure.rug.nl/ws/files/135804458/1_s2.0_S0092867420305006_main.pdfTest -
7دورية أكاديمية
المؤلفون: Cantuti-Castelvetri, Ludovico, Ojha, Ravi, Smura, Teemu, Levanov, Lev, Szirovicza, Leonora, Tobi, Allan, Kallio-Kokko, Hannimari, Österlund, Pamela, Joensuu, Merja, Meunier, Frédéric A, Butcher, Sarah J, Winkler, Martin Sebastian, Pedro, Liliana Domingues, Mollenhauer, Brit, Helenius, Ari, Gökce, Ozgun, Teesalu, Tambet, Hepojoki, Jussi, Vapalahti, Olli, Stadelmann, Christine, Balistreri, Giuseppe, Simons, Mikael, Djannatian, Minou, Franz, Jonas, Kuivanen, Suvi, van der Meer, Franziska, Kallio, Katri, Kaya, Tugberk, Anastasina, Maria
المصدر: Science / Science now 370(6518), 856 - 860 (2020). doi:10.1126/science.abd2985
مصطلحات موضوعية: info:eu-repo/classification/ddc/320, Angiotensin-Converting Enzyme 2, Animals, Antibodies, Monoclonal: immunology, Betacoronavirus: genetics, Betacoronavirus: physiology, COVID-19, Caco-2 Cells, Coronavirus Infections: virology, Female, HEK293 Cells, Host Microbial Interactions, Humans, Lung: metabolism, Male, Metal Nanoparticles, Mice, Inbred C57BL, Mutation, Neuropilin-1: chemistry, Neuropilin-1: genetics, Neuropilin-1: immunology, Neuropilin-1: metabolism, Neuropilin-2: metabolism, Olfactory Mucosa: metabolism, Olfactory Mucosa: virology, Pandemics, Peptide Fragments: metabolism, Peptidyl-Dipeptidase A: genetics
جغرافية الموضوع: DE
الوصف: The causative agent of coronavirus disease 2019 (COVID-19) is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). For many viruses, tissue tropism is determined by the availability of virus receptors and entry cofactors on the surface of host cells. In this study, we found that neuropilin-1 (NRP1), known to bind furin-cleaved substrates, significantly potentiates SARS-CoV-2 infectivity, an effect blocked by a monoclonal blocking antibody against NRP1. A SARS-CoV-2 mutant with an altered furin cleavage site did not depend on NRP1 for infectivity. Pathological analysis of olfactory epithelium obtained from human COVID-19 autopsies revealed that SARS-CoV-2 infected NRP1-positive cells facing the nasal cavity. Our data provide insight into SARS-CoV-2 cell infectivity and define a potential target for antiviral intervention.
العلاقة: info:eu-repo/semantics/altIdentifier/issn/0036-8075; info:eu-repo/semantics/altIdentifier/issn/1095-9203; info:eu-repo/semantics/altIdentifier/pmid/pmid:33082293; info:eu-repo/semantics/altIdentifier/issn/1947-8062; https://pub.dzne.de/record/164307Test; https://pub.dzne.de/search?p=id:%22DZNE-2022-00961%22Test
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8
المؤلفون: James Yarmolinsky, Virginia Díez-Obrero, Tom G Richardson, Marie Pigeyre, Jennifer Sjaarda, Guillaume Paré, Venexia M Walker, Emma E Vincent, Vanessa Y Tan, Mireia Obón-Santacana, Demetrius Albanes, Jochen Hampe, Andrea Gsur, Heather Hampel, Rish K Pai, Mark Jenkins, Steven Gallinger, Graham Casey, Wei Zheng, Christopher I Amos, International Lung Cancer Consortium, PRACTICAL consortium, MEGASTROKE consortium, George Davey Smith, Richard M Martin, Victor Moreno
المصدر: PLoS Medicine, Vol 19, Iss 2, p e1003897 (2022)
Yarmolinsky, J, Díez-Obrero, V, Richardson, T G, Pigeyre, M, Sjaarda, J, Paré, G, Walker, V M, Vincent, E E, Tan, V Y, Obón-Santacana, M, Albanes, D, Hampe, J, Gsur, A, Hampel, H, Pai, R K, Jenkins, M, Gallinger, S, Casey, G, Zheng, W, Amos, C I, International Lung Cancer Consortium, The PRACTICAL Consortium, The MEGASTROKE consortium, Smith, G D, Martin, R M & Moreno, V 2022, ' Genetically proxied therapeutic inhibition of antihypertensive drug targets and risk of common cancers : A mendelian randomization analysis ', PLOS Medicine, vol. 19, no. 2, e1003897 . https://doi.org/10.1371/journal.pmed.1003897Test
the PRACTICAL Consortium 2022, ' Genetically proxied therapeutic inhibition of antihypertensive drug targets and risk of common cancers : A mendelian randomization analysis ', PLoS Medicine, vol. 19, no. 2, e1003897 . https://doi.org/10.1371/journal.pmed.1003897Test
Dipòsit Digital de la UB
Universidad de Barcelonaمصطلحات موضوعية: Male, Polymorphism, Single Nucleotide/drug effects, Antihypertensive Agents/adverse effects, Mendelian Randomization Analysis/methods, Peptidyl-Dipeptidase A/genetics, General Medicine, Receptors, Adrenergic, beta-1/genetics, Blood Pressure/drug effects, Risk Factors, Neoplasms/chemically induced, Hypertension, Genome-Wide Association Study/methods, Humans, Medicine, Female, Hipertensió, ICEP, Solute Carrier Family 12, Member 3/genetics, Càncer, Cancer
الوصف: BackgroundEpidemiological studies have reported conflicting findings on the potential adverse effects of long-term antihypertensive medication use on cancer risk. Naturally occurring variation in genes encoding antihypertensive drug targets can be used as proxies for these targets to examine the effect of their long-term therapeutic inhibition on disease outcomes. Methods and findingsWe performed a mendelian randomization analysis to examine the association between genetically proxied inhibition of 3 antihypertensive drug targets and risk of 4 common cancers (breast, colorectal, lung, and prostate). Single-nucleotide polymorphisms (SNPs) in ACE, ADRB1, and SLC12A3 associated (P < 5.0 x 10(-8)) with systolic blood pressure (SBP) in genome-wide association studies (GWAS) were used to proxy inhibition of angiotensin-converting enzyme (ACE), beta-1 adrenergic receptor (ADRB1), and sodium-chloride symporter (NCC), respectively. Summary genetic association estimates for these SNPs were obtained from GWAS consortia for the following cancers: breast (122,977 cases, 105,974 controls), colorectal (58,221 cases, 67,694 controls), lung (29,266 cases, 56,450 controls), and prostate (79,148 cases, 61,106 controls). Replication analyses were performed in the FinnGen consortium (1,573 colorectal cancer cases, 120,006 controls). Cancer GWAS and FinnGen consortia data were restricted to individuals of European ancestry. Inverse-variance weighted random-effects models were used to examine associations between genetically proxied inhibition of these drug targets and risk of cancer. Multivariable mendelian randomization and colocalization analyses were employed to examine robustness of findings to violations of mendelian randomization assumptions. Genetically proxied ACE inhibition equivalent to a 1-mm Hg reduction in SBP was associated with increased odds of colorectal cancer (odds ratio (OR) 1.13, 95% CI 1.06 to 1.22; P = 3.6 x 10(-4)). This finding was replicated in the FinnGen consortium (OR 1.40, 95% CI 1.02 to 1.92; P = 0.035). There was little evidence of association of genetically proxied ACE inhibition with risk of breast cancer (OR 0.98, 95% CI 0.94 to 1.02, P = 0.35), lung cancer (OR 1.01, 95% CI 0.92 to 1.10; P = 0.93), or prostate cancer (OR 1.06, 95% CI 0.99 to 1.13; P = 0.08). Genetically proxied inhibition of ADRB1 and NCC were not associated with risk of these cancers. The primary limitations of this analysis include the modest statistical power for analyses of drug targets in relation to some less common histological subtypes of cancers examined and the restriction of the majority of analyses to participants of European ancestry. ConclusionsIn this study, we observed that genetically proxied long-term ACE inhibition was associated with an increased risk of colorectal cancer, warranting comprehensive evaluation of the safety profiles of ACE inhibitors in clinical trials with adequate follow-up. There was little evidence to support associations across other drug target-cancer risk analyses, consistent with findings from short-term randomized controlled trials for these medications. Author summary Why was this study done? Angiotensin-converting enzyme (ACE) inhibitors, beta blockers, and thiazide diuretics are commonly prescribed antihypertensive medications.Some epidemiological studies have suggested that long-term use of these medications can increase cancer risk, though findings have been conflicting.Germline genetic variation in genes encoding drug targets can be used to proxy the effect of long-term modulation of these targets on disease endpoints (drug-target mendelian randomization). What did the researchers do and find? We used drug-target mendelian randomization to examine the association of genetically proxied inhibition of the drug targets of ACE inhibitors, beta blockers, and thiazide diuretics with risk of 4 of the most common adult cancers (breast, colorectal, lung, and prostate) in up to 289,612 cancer cases and 291,224 controls.We found evidence that genetically proxied inhibition of the drug target for ACE inhibitors was associated with an increased risk of colorectal cancer.There was little evidence that genetically proxied inhibition of the drug target for ACE inhibitors was associated with risk of the other cancers examined or evidence for an association of genetically proxied inhibition of drug targets for beta blockers and thiazide diuretics with risk of all 4 cancers examined. What do these findings mean? These findings provide support for a link between long-term inhibition of the drug target for ACE inhibitors and colorectal cancer risk, highlighting the need to evaluate the safety profiles of these medications in clinical trials with adequate follow-up length.Prior to confirmation of an effect of ACE inhibitor use on colorectal cancer risk in clinical trials, these findings should not alter clinical practice for ACE inhibitor prescribing.
وصف الملف: application/pdf
الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::58ebdcff10cb8f88caaecd212f39594eTest
https://doaj.org/article/34b1a0c7008a49a584262cd8aef7a5ecTest -
9دورية أكاديمية
المؤلفون: Susilo, Hendri, Pikir, Budi Susetyo, Thaha, Mochammad, Alsagaff, Mochamad Yusuf, Suryantoro, Satriyo Dwi, Wungu, Citrawati Dyah Kencono, Wafa, Ifan Ali, Pakpahan, Cennikon, Oceandy, Delvac
المصدر: Susilo , H , Pikir , B S , Thaha , M , Alsagaff , M Y , Suryantoro , S D , Wungu , C D K , Wafa , I A , Pakpahan , C & Oceandy , D 2022 , ' The Effect of Angiotensin Converting Enzyme (ACE) I/D Polymorphism on Atherosclerotic Cardiovascular Disease and Cardiovascular Mortality Risk in Non-Hemodialyzed Chronic Kidney Disease : The Mediating Role of Plasma ACE Level ' , Genes , vol. 13 , no. 7 . https://doi.org/10.3390/genes13071121Test
مصطلحات موضوعية: Atherosclerosis/genetics, Cardiovascular Diseases/genetics, Cross-Sectional Studies, Humans, Peptidyl-Dipeptidase A/genetics, Polymorphism, Genetic, Renal Insufficiency, Chronic/genetics
الوصف: The association between angiotensin-converting enzyme insertion/deletion (ACE I/D) polymorphisms and plasma ACE levels may allow for the optimization of a preventive intervention to reduce cardiovascular morbidity and mortality in the chronic kidney disease (CKD) population. In this study, we aimed to analyze the association between ACE I/D polymorphism and cardiovascular mortality risk among non-hemodialyzed chronic kidney disease patients. This cross-sectional study examined 70 patients of Javanese ethnic origin with stable CKD who did not receive hemodialysis. ACE I/D polymorphisms, plasma ACE levels, atherosclerotic cardiovascular disease (ASCVD) risk, and cardiovascular mortality risk were investigated. As per our findings, the I allele was found to be more frequent (78.6) than the D allele (21.4), and the DD genotype was less frequent than the II genotype (4.3 vs. 61.4). The ACE I/D polymorphism had a significant direct positive effect on plasma ACE levels (path coefficient = 0.302, p = 0.021). Similarly, plasma ACE levels had a direct and significant positive effect on the risk of atherosclerotic cardiovascular disease (path coefficient = 0.410, p = 0.000). Moreover, atherosclerotic cardiovascular disease risk had a significant positive effect on cardiovascular mortality risk (path coefficient = 0.918, p = 0.000). The ACE I/D polymorphism had no direct effect on ASCVD and cardiovascular mortality risk. However, our findings show that the indirect effects of high plasma ACE levels may be a factor in the increased risk of ASCVD and cardiovascular mortality in Javanese CKD patients.
الإتاحة: https://doi.org/10.3390/genes13071121Test
https://research.manchester.ac.uk/en/publications/e8733e1d-2821-4acb-aedc-e2d055e97a02Test -
10دورية أكاديمية
المؤلفون: Chiriacò, Martina, Tricò, Domenico, Leonetti, Simone, Petrie, John R., Balkau, Beverley, Højlund, Kurt, Pataky, Zoltan, Nilsson, Peter M, Natali, Andrea, RISC Investigators
المصدر: ISSN: 0194-911X ; Hypertension, vol. 79, no. 1 (2022) p. 36-46.
مصطلحات موضوعية: info:eu-repo/classification/ddc/616, Angiotensin-converting enzyme, Sex characteristics, Adiposity / genetics, Adult, Blood Pressure / genetics, Body Mass Index, Female, Genetic Predisposition to Disease, Genotype, Humans, Hypertension / genetics, INDEL Mutation, Male, Middle Aged, Peptidyl-Dipeptidase A / genetics, Polymorphism, Single Nucleotide, Sex Factors, Waist Circumference
الوصف: The pathophysiological link between adiposity and blood pressure is not completely understood, and evidence suggests an influence of sex and genetic determinants. We aimed to identify the relationship between adiposity and blood pressure, independent of a robust set of lifestyle and metabolic factors, and to examine the modulating role of sex and Angiotensin-Converting Enzyme (ACE) insertion/deletion (I/D) polymorphisms. In the Relationship Between Insulin Sensitivity and Cardiovascular Disease (RISC) study cohort, 1211 normotensive individuals, aged 30 to 60 years and followed-up after 3.3 years, were characterized for lifestyle and metabolic factors, body composition, and ACE genotype. Body mass index (BMI) and waist circumference (WC) were independently associated with mean arterial pressure, with a stronger relationship in women than men (BMI: r =0.40 versus 0.30; WC: r =0.40 versus 0.30, both P <0.01) and in individuals with the ID and II ACE genotypes in both sexes ( P <0.01). The associations of BMI and WC with mean arterial pressure were independent of age, sex, lifestyle, and metabolic variables (standardized regression coefficient=0.17 and 0.18 for BMI and WC, respectively) and showed a significant interaction with the ACE genotype only in women ( P =0.03). A 5 cm larger WC at baseline increased the risk of developing hypertension at follow-up only in women (odds ratio, 1.56 [95% CI, 1.15–2.10], P =0.004) and in II genotype carriers (odds ratio, 1.87 [95% CI, 1.09–3.20], P =0.023). The hypertensive effect of adiposity is more pronounced in women and in people carrying the II variant of the ACE genotype, a marker of salt sensitivity.
العلاقة: info:eu-repo/semantics/altIdentifier/pmid/34689596; https://archive-ouverte.unige.ch/unige:169210Test; unige:169210
